[Federal Register Volume 62, Number 92 (Tuesday, May 13, 1997)]
[Rules and Regulations]
[Pages 26225-26228]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12461]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 87G-0351]
Food Additives Permitted for Direct Addition to Food for Human
Consumption; 1,3-Butylene Glycol
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of 1,3-butylene glycol
as a formulation and processing aid in the manufacture of edible
sausage casings. This action is in response to a petition filed by
Teepak, Inc.
DATES: Effective May 13, 1997; written objections and requests for a
hearing by June 12, 1997. The Director of the Office of the Federal
Register approves the incorporation by reference in accordance with 5
U.S.C. 552(a) and 1 CFR part 51 of a certain publication listed in new
Sec. 172.712, effective May 13, 1997.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: James C. Wallwork, Center for Food
Safety and Applied Nutrition (HFS-215), Food and Drug Administration,
200 C St. SW., Washington, DC 20204-0001, 202-418-3078.
SUPPLEMENTARY INFORMATION:
I. Background
In accordance with the procedures described in Sec. 170.35 (21 CFR
170.35), Teepak, Inc., 915 North Michigan Ave., Danville, IL 61832-
0597, submitted a petition (GRASP 7G0332) requesting that 1,3-butylene
glycol be affirmed as generally recognized as safe (GRAS) for use in
food as a formulation and processing aid, when used in accordance with
current good manufacturing practice.
FDA published a notice of filing of this petition in the Federal
Register of November 23, 1987 (52 FR 44936), and gave interested
parties an opportunity to submit comments concerning the petition to
the Dockets Management Branch (address above). FDA received no comments
in response to that notice.
After the petition was filed, the petitioner amended the petition
to limit the scope of the requested GRAS affirmation. As amended, the
petition asks FDA to affirm 1,3-butylene glycol as GRAS for use only as
a formulation and processing aid in the manufacture of edible sausage
casings.
II. Standard for Evaluation of Petition
Under Sec. 170.30 (21 CFR 170.30), general recognition of safety
may be based only on the views of experts qualified by scientific
training and experience to evaluate the safety of substances added to
food. The basis of such views may be either: (1) Scientific procedures,
or (2) in the case of a substance used in food prior to January 1,
1958, experience based on common use in food (Sec. 170.30(a)). General
recognition of safety based upon scientific procedures requires the
same quantity and quality of scientific evidence as is required to
obtain approval of the substance as a food additive and ordinarily is
to be based upon published studies, which may be corroborated by
unpublished studies and other data and information (Sec. 170.30(b)). In
its petition, Teepak, Inc., has not claimed a history of common use in
food before 1958, but rather has relied upon scientific procedures,
primarily published scientific papers, to support its claim that 1,3-
butylene glycol is GRAS.
In reviewing the data in the petition and other relevant material,
FDA noted that the published studies on the safety of 1,3-butylene
glycol are of varying quality. As discussed in section IV. of this
document, the agency believes that the available data, taken together,
establish the safety of 1,3-butylene glycol for the limited use
requested in the petition. However, FDA does not believe that the data
are sufficient to show that the basis for such a safety determination
is generally recognized by experts in the field.
Thus, in accordance with 21 CFR 170.35(c)(5) and 170.38, the agency
has determined that the requested use of 1,3-butylene glycol cannot be
considered GRAS based upon scientific procedures and that the compound
is a food additive subject to section 409 of the Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C. 348). FDA notified the petitioner
of this conclusion and the firm agreed that 1,3-butylene glycol could
be evaluated as a food additive rather than as a GRAS ingredient.
III. Introduction
A. Identity
1,3-Butylene glycol
(CH2OHCH2CHOHCH3, CAS Reg. No.
[[Page 26226]]
107-88-0, and molecular weight 90.12) is the common name for 1,3-
dihydroxybutane or 1,3-butanediol. It is a clear, colorless,
hygroscopic, viscous liquid almost without odor.
B. Regulated Food and Packaging Uses
1,3-Butylene glycol is regulated for use under 21 CFR 173.220 1,3-
Butylene glycol as a solvent for natural and synthetic flavoring
substances, except where food standards preclude its use. Also, 1,3-
butylene glycol is regulated for use in polyester formation under 21
CFR 175.320 Resinous and polymeric coatings for polyolefin films and as
a reactant under 21 CFR 177.1680 Polyurethane resins in the preparation
of resins for use in contact with dry bulk foods.
IV. Safety
A. Manufacturing Process
1,3-Butylene glycol is produced through the controlled aldol
condensation of acetaldehyde in the presence of dilute aqueous sodium
hydroxide. The first reaction product, a trimer of acetaldehyde, is
decomposed to a dimer, acetaldol (3-hydroxy-butyraldehyde), during the
neutralization of the excess sodium hydroxide with dilute acetic acid.
The unreacted acetaldehyde is removed by distillation. Acetaldol is
then reduced to butylene glycol by hydrogenation in the presence of a
nickel catalyst. 1,3-Butylene glycol thus produced is purified in a
series of vacuum distillation towers. The product is manufactured to
conform to the identity and specifications listed in the monograph
entitled ``1,3-Butylene Glycol'' in the Food Chemicals Codex, 4th ed.
(1996), p. 52.
B. Proposed Use in Food
The petition contains data demonstrating that 1,3-butylene glycol
is effective in reducing breakage in manufactured sausage casings. The
petition also contains data demonstrating that the petitioned substance
is most effective at levels of 5 to 15 percent of the liquid phase of
the casing (equivalent to 2 to 6 percent of the total casing weight).
Included in the petition are data demonstrating that at levels higher
than 6 percent, 1,3-butylene glycol sausage casings become more
susceptible to breakage. Thus, the petition provides data demonstrating
that the proposed ingredient is technologically self-limiting.
C. Consumer Exposure
Using sausage intake data from the Market Research Corp. of America
(Ref. 1) and assuming from information submitted with the petition that
1 percent of the weight of sausage is casing made with 6 percent 1,3-
butylene glycol, FDA estimates that exposure to the proposed ingredient
is 6.0 milligrams/person/day (mg/p/d) (mean) and 12 mg/p/d (90th
percentile) for the 2+ years age group. For the 2- to 5-year-old age
group subcategory, FDA estimates that exposure is 4.5 mg/p/d (mean) and
8.5 mg/p/d (90th percentile).
D. Toxicology
To provide evidence of the safety of 1,3-butylene glycol for the
petitioned use, the petitioner provided published and unpublished
reproduction and chronic feeding studies in rats and dogs, as well as a
number of published short-term nutrition and metabolism studies. In
addition, an agency-initiated literature search identified a
reproduction study with 1,3-butylene glycol published in 1990.
A published 2-year dietary feeding study (Ref. 2) in beagle dogs
reported no visible adverse effects on appearance, behavior, growth,
food intake, urinalysis, hematology or serum biochemistry that could be
attributed to treatment with 1,3-butylene glycol. The diets of male and
female dogs were treated with the petitioned substance at 118, 228, and
613 mg/kilogram body weight/day (mg/kg bw/d) for males and 101, 228,
and 732 mg/kg bw/d for females. Although microscopic lesions were
observed in testes and lymph nodes of males after 1 and 2 years'
treatment, FDA concludes that the lesions do not appear to be of
pathological significance. Lesions of the type and severity observed
are frequent incidental findings in dogs. Moreover, no significant
difference in appearance between lesions in control and treated animals
could be derived from the histopathological descriptions of the tissues
examined. Therefore, the agency finds that the incidence of gross
pathological lesions is unrelated to treatment and that this study
supports a no-effect level of 700 mg/kg bw/d, the highest dose in the
study.
The agency concludes that data from a published 2-year dietary
feeding study (Ref. 2) in Sprague-Dawley rats cannot be used to
establish the safety of 1,3-butylene glycol. The study had insufficient
statistical power to detect an adverse response to 1,3-butylene glycol
because an inadequate number of rats was used and widespread disease
killed most of the rats during the second year of the study.
A published reproduction study (Ref. 3) in Long-Evans rats, treated
by gavage with 1,3-butylene glycol (0, 706, 4,236, and 7,060 mg/kg bw/
d) during days 6 to 15 of gestation, also reported no treatment-related
effects on a variety of reproduction parameters (litter weight and
size, crown-rump length, corpora lutea, implantation sites, sex
distribution, intrauterine deaths, total malformed pups or incidence of
litters with malformed pups). However, the researchers reported an
increased incidence of low body weights and sternebral anomalies in
pups from high-dose mothers, indicating a possible teratogenic effect
from exposure to 1,3-butylene glycol. The full significance of the
effects of the treatment of rats with 1,3-butylene glycol, though,
cannot be determined from the available data. FDA finds that the data
are insufficient to determine whether the observed anomalies were
caused by the treatment-related reductions in birth weight or by a
teratogenic effect of the additive. However, because the observed low
body weights and sternebral anomalies occurred only in high-dose
groups, the agency concludes that a no-effect level can be set from
doses employed with mid-dose rats at 4,200 mg/kg bw/d.
A number of published and unpublished nutritional and metabolic
studies with 1,3-butylene glycol were also provided (Refs. 4 through
21). Within the limited scope of those studies no significant
toxicological effects were reported except in a human clinical study
(Ref. 21). In that study, 1,3-butylene glycol fed to young male and
female subjects (250 mg/kg bw/d in bread for four separate 7-day
periods) was reported to significantly depress blood glucose (lowered
by 12 percent relative to controls). The 1,3-butylene glycol-induced
glucose reduction did not involve insulin or growth hormone, although
its mechanism could not be determined. As discussed in section IV.D.1.
of this section, the reduction in blood glucose would not be expected
to occur at the low levels estimated for human dietary exposure from
the proposed use of 1,3-butylene glycol.
Ordinarily, chronic studies in rodent and nonrodent species are
needed to establish the safety of direct food ingredients (Ref. 22).
Although the petitioner did not submit an acceptable chronic dietary
rodent study, FDA concludes that the toxicological data submitted are
adequate to establish the safety of the use of 1,3-butylene glycol in
edible sausage casings, for the following reasons:
1. The metabolism of 1,3-butylene glycol is well understood. In the
rat, 1,3-butylene glycol is metabolized in the liver cytosol in a
manner similar to ethanol (Refs. 13 and 16). In the intact rat and in
tissue slices, it is converted
[[Page 26227]]
to acetoacetate and -hydroxybutyrate, which are normal
intermediates in fat metabolism. In the kidney, 1,3-butylene glycol
blocks gluconeogenesis at the conversion of 3-phosphoglycerate to
glyceraldehyde-3-phosphate (Ref. 14). This metabolic blockage is
responsible for the reduction in serum glucose that occurs when 1,3-
butylene glycol is consumed at sufficiently high levels. At consumption
levels that would be expected from the proposed use, however, 1,3-
butylene glycol would not be expected to inhibit gluconeogenesis in the
kidney. In addition, from an examination of the scientific literature
on the metabolism of 1,3-butylene glycol, which is well understood and
documented (Refs. 16 and 21), there is no indication that 1,3-butylene
glycol would be expected to have any carcinogenic potential. Therefore,
FDA concludes that a chronic rodent study is not necessary to support
the safety of the proposed use of 1,3-butylene glycol.
2. To ensure an adequate margin of safety, FDA applied a 1,000-fold
safety factor (rather than the normal 100-fold safety factor) to the
no-effect level from the dog study (Ref. 2) to compensate for the lack
of an acceptable chronic rodent study for 1,3-butylene glycol. Applying
a 1,000-fold safety factor to the no-effect level from the dog study
gives an acceptable daily intake (ADI) for 1,3-butylene glycol of 0.7
mg/kg bw. Although an adverse metabolic effect (decreased serum
glucose) was reported in humans consuming 250 mg 1,3-butylene glycol/kg
bw, it is unlikely that any such metabolic effects would be observed at
the ADI, which is 350-fold lower. Furthermore, for 1,3-butylene glycol,
the ADI (0.7 mg/kg bw) is greater than the daily exposure estimates of
0.1 mg/kg bw (mean) and 0.2 mg/kg bw (90th percentile) for adults,
assuming a bw of 60 kg, and 0.3 mg/kg bw (mean) and 0.6 mg/kg bw (90th
percentile) for 2- to 5-year-olds, assuming a body weight of 15 kg.
Therefore, the agency concludes that the level of exposure resulting
from the petitioned use of 1,3-butylene glycol is safe.
V. Conclusion on Safety
FDA has evaluated the data in the petition and other relevant
material regarding the use of 1,3-butylene glycol as a formulation and
processing aid in sausage casings and concludes that the substance
produces the intended technical effects and is safe under the proposed
conditions of use. Therefore, the agency is amending the food additive
regulations to provide for the requested use.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition
and the documents that FDA considered and relied upon in reaching its
decision to approve the petition are available for inspection at the
Center for Food Safety and Applied Nutrition by appointment with the
information contact person listed above. As provided in Sec. 171.1(h),
the agency will delete from the documents any materials that are not
available for public disclosure before making the documents available
for inspection.
VI. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. FDA has concluded that the action will not have
a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday.
VII. Objections
Any person who will be adversely affected by this regulation may at
any time on or before June 12, 1997, file with the Dockets Management
Branch (address above) written objections thereto. Each objection shall
be separately numbered, and each numbered objection shall specify with
particularity the provisions of the regulation to which objection is
made and the grounds for the objection. Each numbered objection on
which a hearing is requested shall specifically so state. Failure to
request a hearing for any particular objection shall constitute a
waiver of the right to a hearing on that objection. Each numbered
objection for which a hearing is requested shall include a detailed
description and analysis of the specific factual information intended
to be presented in support of the objection in the event that a hearing
is held. Failure to include such a description and analysis for any
particular objection shall constitute a waiver of the right to a
hearing on the objection. Three copies of all documents shall be
submitted and shall be identified with the docket number found in
brackets in the heading of this document. Any objections received in
response to the regulation may be seen in the Dockets Management Branch
between 9 a.m. and 4 p.m., Monday through Friday.
VIII. References
The following references have been placed on display in the Dockets
Management Branch (address above ) and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum from M. DiNovi, Chemistry Review Branch, to R. L.
Martin, Direct Additives Branch, dated November 8, 1988.
2. Scala, R. A., and O. E. Paynter, ``Chronic Oral Toxicity of
1,3-Butanediol,'' Toxicology and Applied Pharmacology, 10:160-164,
1967.
3. Mankes, R. F., V. Renak, J. Fieseher, and R. LeFevre,
``Birthweight Depression in Male Rats Contiguous to Male Siblings in
Utero Exposed to High Doses of 1,3-Butanediol During
Organogenesis,'' Journal of the American College of Toxicology,
5:189-196, 1986.
4. Dymsza, H. A., ``Nutritional Application and Implication of
1,3-Butanediol,'' Federation Proceedings, 34:2167-2170, 1975.
5. Giron, H. M., ``Some Aspects of the Utilization of 1,3-Diols
as Synthetic Dietary Energy Sources'' (thesis for master of science
degree), Massachusetts Institute of Technology, August 1968.
6. Food and Drug Research Laboratories, Inc., Morgareidge, K.,
``Utilization of 1,3-Butylene Glycol in Dogs,'' November 1, 1972.
7. Mehlman, M. A., ``Synthetic Food Additives as a Source of
Calories: 1,3-Butanediol,'' Federation Proceedings, 34:2166, 1975.
8. Miller, S. A., and H. A. Dymsza, ``Utilization by the Rat of
1,3-Butanediol as a Synthetic Source of Dietary Energy,'' Journal of
Nutrition, 91:79-88, 1967.
9. Stoewsand, G. S., H. A. Dymsza, M. A. Kilmore, and S. M.
Swift, ``Plasma Lipid Changes in Exercised Dogs Fed 1,3-
Butanediol,'' Federation Proceedings, 25:608, 1966 (abstract).
10. Young, J. W., ``Use of 1,3-Butanediol for Lactation and
Growth in Cattle,'' Federation Proceedings, 34:2177-2181, 1975.
11. Mackerer, C. R., R. N. Saunders, J. R. Haettinger, and M. A.
Mehlman, ``Influence of 1,3-Butanediol on Blood Glucose
Concentration and Pancreatic Insulin Content of Streptozotocin-
Diabetic Rats,'' Federation Proceedings, 34:2191-2196, 1975.
12. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Metabolic
Control of Enzymes in Normal, Diabetic and Diabetic Insulin Treated
Rats Utilizing 1,3-Butanediol'' (undated).
13. Mehlman, M. A., R. B. Tobin, H. K. J. Hahn, V. DeVore, and
L. Kleager, ``Metabolic Fate of 1,3-Butanediol (BD) in the Rat,''
Omaha, NE (undated).
14. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Influence
of Dietary 1,3-Butanediol on Metabolites and Enzymes Involved in
Gluconeogenesis and Lipogenesis in Rats,'' Journal of Nutrition,
100:1341-1346, 1970.
15. Mehlman, M. A., R. B. Tobin, and C. R. Mackerer, ``1,3-
Butanediol Catabolism in the Rat,'' Federation Proceedings, 34:2182-
2185, 1975.
16. Nahapetian, A., ``Metabolism in Vivo of 1,3-Butanediol in
the Rat'' (thesis for doctor of science degree), Massachusetts
Institute of Technology, September 1971.
17. Parker, M. M. (under the supervision of Myron A. Mehlman),
``Metabolic Effects of 1,3-Butanediol,'' Omaha, NE, August 1972.
[[Page 26228]]
18. Romsos, D. R., P. S. Belo, and G. A. Leveille, ``Butanediol
and Lipid Metabolism,'' Federation Proceedings, 34:2186-2190, 1975.
19. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``The
Metabolism of 1,3-Butanediol'' (undated).
20. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``Metabolic
Fate of 1,3-Butanediol in the Rat: Conversion to -
Hydroxybutyrate,'' Journal of Nutrition, 101:1719-1726, 1971.
21. Tobin, R. B., M. A. Mehlman, C. Kies, H. M. Fox, and J. S.
Soeldner, ``Nutritional and Metabolic Studies in Humans With 1,3-
Butanediol,'' Federation Proceedings, 34:2171-2176, 1975.
22. ``Toxicological Principles for the Safety Assessment of
Direct Food Additives and Color Additives Used in Food'' in
``Redbook,'' Center for Food Safety and Applied Nutrition, Food and
Drug Administration, 1982. Available through National Technical
Information Service (NTIS), 5285 Port Royal Rd., Springfield, VA
22161, order number PB-83-170696. Revised draft is available from
the Office of Premarket Approval (HFS-206), 200 C St. SW.,
Washington, DC 20204-0001.
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by reference, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Director, Center for Food Safety and Applied
Nutrition, 21 CFR part 172 is amended as follows:
PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
1. The authority citation for 21 CFR part 172 continues to read as
follows:
Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371,
379e).
2. New Sec. 172.712 is added to subpart H to read as follows:
Sec. 172.712 1,3-Butylene glycol.
The food additive 1,3-butylene glycol (CAS Reg. No. 107-88-0) may
be safely used in food in accordance with the following prescribed
conditions:
(a) It is prepared by the aldol condensation of acetaldehyde
followed by catalytic hydrogenation.
(b) The food additive shall conform to the identity and
specifications listed in the monograph entitled ``1,3-Butylene Glycol''
in the Food Chemicals Codex, 4th ed. (1996), p. 52, which is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from the Office of Premarket Approval,
Center for Food Safety and Applied Nutrition, 200 C St. SW.,
Washington, DC 20204-0001, or may be examined at the Center for Food
Safety and Applied Nutrition's Library, Food and Drug Administration,
200 C St. SW., rm. 3321, Washington, DC, or at the Office of the
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.
(c) It is used in the manufacture of sausage casings as a
formulation aid as defined in Sec. 170.3(o)(14) of this chapter and as
a processing aid as defined in Sec. 170.3(o)(24) of this chapter.
Dated: April 14, 1997.
Fred R. Shank,
Director, Center for Food Safety and Applied Nutrition.
[FR Doc. 97-12461 Filed 5-12-97; 8:45 am]
BILLING CODE 4160-01-F